While epidemiological data has linked COPD and lung cancer, and both diseases are causally related to tobacco smoke exposure, the molecular mechanisms that connect these diseases remain unclear. Our proposal leverages the molecular field of injury that occurs throughout the airway and lung tissue of smokers in order to explore the molecular links between these two smoking-related lung diseases. We hypothesize that COPD-related oncogenic processes can be monitored non-invasively through airway epithelial profiling, and that molecular signatures of these processes and pathways may be detected prior to the development of lung cancer. Our prior work has demonstrated that lung cancer and COPD disease processes can be monitored in cytologically-normal airway epithelium that is remote to the site of disease formation and that airway gene expression can serve as a clinically-relevant early detection biomarker for lung cancer among smokers. We have preliminary data that has identified genes whose expression profiles vary uniquely with COPD in tumor tissue and that these changes can also be detected in the airway, suggesting that genomic alterations in the airway and lung tissue of smokers reflects COPD-specific patterns of lung carcinogenesis. In this proposal, we will perform gene- expression, copy number, and DNA-methylation profiling studies in four unique and well- characterized cohorts of frozen lung and airway tissues in order to identify COPD-specific processes involved in lung carcinogenesis in the tumor and airway. We will initially identify molecular pathways and processes related to COPD that contribute to lung carcinogenesis through integration of gene expression and methylation data from lung tissue samples. We will then determine whether large-airway epithelium can serve as a surrogate for lung tissue and develop an airway biomarker for detecting lung cancer in the context of COPD. Finally, we will test the hypothesis that biomarkers reflecting COPD-related lung carcinogenesis can be measured in airway epithelium prior to development of lung cancer. Understanding the molecular connections between COPD and lung cancer in the field of injury will allow us to develop improved biomarkers for lung cancer surveillance among smokers with COPD and develop targeted lung-cancer chemoprevention strategies that interfere with lung-cancer promoting aspects of COPD pathogenesis.